Recent Advances in the Biology and Treatment of Acute Promyelocytic Leukemia, страница 6

Should Patients Receive Maintenance Therapy? (and if so, with what?)

The role of maintenance therapy in APL⁷⁰ continues to be an area of active study in both North America and in Europe.²-³-⁸⁶ In the North American Intergroup trial,² patients who completed consolidation were randomized to observation alone or to 1 year of daily ATRA. There was a suggestion for a benefit of maintenance ATRAboth in patients who received chemotherapy only for induction and in those who received induction therapy with ATRA (Fig 2). The preliminary results of the European APL 93 trial also support the use of maintenance therapy with either ATRA, chemotherapy (low-dose mercaptopurine and methotrexate), or both.⁶⁶ These preliminary results, combined with an earlier report,⁷⁰ suggest that some type of maintenance therapy may benefit patients withAPL. The upcoming North American Intergroup trial will include an ATRA maintenance arm for all patients, with a randomization between intermittent (pulsed) and continuous ATRA. For patients not enrolled on protocol, it seems prudent to consider 1 year of maintenance ATRA, either continuously or in a pulsed schedule (eg, 15 days every 3 months or 7 days on, 7 days off); one of the latter regimens is pharmacologi-cally more appealing, but neither has been tested in a published clinical trial.

Zs Detection of Minimal Residual Disease by RT-PCR Worthwhile?

The sensitivity and specificity of the RT-PCR assay for detection of the APL-spectfic PML-RARa and RARtt-PML transcripts have led to its widespread use in both the diagnosis and monitoring of APL. While there is little disagreement regarding the utility of this assay in assisting with the diagnosis of APL, its role in minimal residual disease (MRD) detection remains under study, and in fact will be one of the central questions of the upcoming North American Intergroup APL trial. There are a number of complex technical and clinical issues that remain to be resolved, primary among these the complete lack of standardization among laboratories that perform the PML-RARa and RARa-PML RT-PCR assays; this lack of standardization precludes extrapolation of results from a single laboratory to a larger clinical setting. It is imperative, and would seem self-evident, that patients not be subjected to intensive therapeutic regimens based on the results of an assay that has not yet been standardized. With these caveats, it is nevertheless useful to briefly review the current status of MRD detection in APL using RT-PCR for detection of PML-RARa and/or RAR«-PML transcripts.

The key technical issue, all else being equal, is sensitivity, while the key clinical issue is timing. At a relatively low level of sensitivity (ie, a levelthat can detect one leukemia cell in ID⁴ normal bone marrow cells), one or more positive PML-RARa assays at the end of consolidation probably predicts relapse.⁷¹ In the study by Lo Coco et al,⁷¹ 205 patients had aerial RT-PCR monitoring after completing consolidation. Among 177 patients with s two negative tests, only two relapses occurred, whereas relapse was seen in 26 of 28 patients with s two positive tests.⁷¹ The median time to relapse after the first positive RT-PCR test was 3 months,⁷¹ suggesting that frequent bone marrow aspirates would need to be performed for this insensitive test to be useful. Using a more sensitive PML-RARtt assay capable of detecting one leukemic cell in 10⁶ or 10⁶ normal cells, we have detected several patients (two of nine to date) who are RT-PCR-positive, but who remain in long-term CR (R. Gallagher, J. Slack, and C. Willman, unpublished data, May 1997). Furthermore, using an RT-PCR assay (sensitivity, one in 5 x 10⁵) to detect the reciprocal translocation, RARa-PML, Tobal et al⁷² have reported a positive assay in six of 18 long-term CR patients, two of whom had undergone allogeneic bone marrow transplantation. We have obtained similar results (R. Galla-gher, J. Slack, and C. Willman, unpublished data, May 1997). It should also be stressed that a negative assay, performed at a low sensitivity level (eg, one in 10⁴), does not assure continued CR. In a study by Grimwade et al,⁷³ among 12 patients who ultimately relapsed despite state-of-the-art APL therapy, nine had had at least one preceding negative PML-RARa RT-PCR assay. RT-PCR assay be performed to provide the most clinically relevant information? Recent studies in other hematologic malignancies suggest that there is a level of MRD at which host immunologic mechanisms can provide tumor control.⁷⁴ Defining this level in APL represents the next and perhaps most difficult challenge for investigators in this field.